EP1856057B1 - Tetrahydroindolone and tetrahydroindazolone derivatives - Google Patents

Tetrahydroindolone and tetrahydroindazolone derivatives Download PDF

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Publication number
EP1856057B1
EP1856057B1 EP06736330.9A EP06736330A EP1856057B1 EP 1856057 B1 EP1856057 B1 EP 1856057B1 EP 06736330 A EP06736330 A EP 06736330A EP 1856057 B1 EP1856057 B1 EP 1856057B1
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EP
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Prior art keywords
oxo
tetrahydro
benzamide
trimethyl
amino
Prior art date
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Expired - Lifetime
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EP06736330.9A
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German (de)
English (en)
French (fr)
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EP1856057A1 (en
Inventor
Kenneth He Huang
Jeron Eaves
James Veal
Thomas Barta
Lifeng Geng
Lindsay Hinkley
Gunnar Hanson
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Esanex Inc
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Serenex Inc
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Priority to SI200631875T priority Critical patent/SI1856057T1/sl
Priority to EP11173186.5A priority patent/EP2380879B1/en
Priority to PL06736330T priority patent/PL1856057T3/pl
Publication of EP1856057A1 publication Critical patent/EP1856057A1/en
Application granted granted Critical
Publication of EP1856057B1 publication Critical patent/EP1856057B1/en
Priority to CY20151100025T priority patent/CY1116636T1/el
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Expired - Lifetime legal-status Critical Current

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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
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Definitions

  • Heat-shock protein 90 (HSP-90) is a cellular chaperone protein required for the activation of several eukaryotic protein kinases, including the cyclin-dependent kinase CDK4.
  • Geldanamycin an inhibitor of the protein-refolding activity of HSP-90, has been shown to have antiproliferative and antitumor activities.
  • the invention further provides compounds for use in methods of treating a subject suffering from a disease or disorder of proteins that are either client proteins for HSP-90 or indirectly affect its client proteins, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound or salt of Formula XXV.
  • R 3 and R 4 are independently hydrogen, halo, or -N(H)R Z1 , wherein R Z1 is a C 1 -C 14 alkyl group where up to five of the carbon atoms in the alkyl group are optionally replaced independently by R 22 , carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO 2 , or SO, with the proviso that two O atoms, two S atoms, or an O and S atom are not immediately adjacent each other, wherein R Z1 is optionally substituted at any available position with C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, hydroxy, carboxy, carboxamido, oxo, halo, amino, C 1 -C 6 alkoxy, mono- or di-(C 1 -C 10 )alkylamino, -OC 1 -C 10 alkyl-Z
  • More preferred compounds of the invention are those of Formula XXV wherein
  • Still other preferred compounds of Formula IX include those where R 3 and R 4 are independently hydrogen, halo, or - Z 1 R Z1 , wherein Z 1 is -0- or -NH-; and R Z1 is a C 1 -C 14 alkyl group where up to five of the carbon atoms in the alkyl group are optionally replaced independently by R 22 , carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO 2 , or SO, with the proviso that two 0 atoms, two S atoms, or an 0 and S atom are not immediately adjacent each other, wherein R Z1 is optionally substituted at any available position with C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino, cyano, nitro,
  • Still other preferred compounds of Formula XVIII are those where R 3 and R 4 are both -H; and X 4 is N-OH.
  • the invention provides compounds formula XXV, wherein X 1 is N; R 4 is H; R 3 is -N(H)R Z1 , wherein R Z1 is a C 1 -C 14 alkyl group where up to five of the carbon atoms in the alkyl group are optionally replaced independently by R 22 , carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO 2 , or SO, with the proviso that two 0 atoms, two S atoms, or an O and S atom are not immediately adjacent each other, wherein R Z1 is optionally substituted at any available position with C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino, cyano, nitro, -SH, -
  • the invention provides compounds formula XXV, wherein X 1 is CR 11 , wherein R 11 is hydrogen, halogen, cyano, nitro, -C(O)R C' , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 haloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl (C 1 -C 10 )alkyl, heterocycloalkyl, aryl, or heteroaryl, wherein R C' is -C 1 -C 6 alkyl, -OR C" , or -N(R CN ) 2 , wherein R C" is -H, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 3 -C 7 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl
  • the invention provides compounds formula XXV, wherein X 1 is CR 11 , wherein R 11 is hydrogen, halogen, cyano, nitro, -C(O)R C' , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 haloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl (C 1 -C 10 )alkyl, heterocycloalkyl, aryl, or heteroaryl, wherein R C' is -C 1 -C 6 alkyl, -OR C" , or -N(R CN ) 2 , wherein R C" is -H, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 3 -C 7 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl
  • the invention encompasses the use of a therapeutically effective amount of a compound or salt of Formula I for the preparation of a medicament for reducing the level of infection caused by Plasmodium falciparum in a subject in need of such treatment
  • test compounds for HSP-90 were determined as follows: Protein mixtures obtained from a variety of organ tissues (for example: spleen, liver and lung) were reversibly bound to a purine affinity column to capture purine-binding proteins, especially HSP-90. The purine affinity column was washed several times, and then eluted with 20 ⁇ M, 100 ⁇ M, and 500 ⁇ M of test compound. Compounds of Formula I elute HP-90 in a dose-dependent manner vs. a control elution using dimethylsulfoxide. The elution profile of Formula I compounds was determined by 1-dimensional SDS polyacrylamide gel electrophoresis.

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EP06736330.9A 2005-02-25 2006-02-27 Tetrahydroindolone and tetrahydroindazolone derivatives Expired - Lifetime EP1856057B1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
SI200631875T SI1856057T1 (sl) 2005-02-25 2006-02-27 Tetrahidroindolonski in tetrahidroindazolonski derivati
EP11173186.5A EP2380879B1 (en) 2005-02-25 2006-02-27 Tetrahydroindolone and tetrahydroindazolone derivatives
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